The selective cathepsin K inhibitor odanacatib (ODN) is currently in development for the treatment of postmenopausal osteoporosis. Our goal was to evaluate the effects of ODN vs alendronate (ALN) on bone mass and strength of lumbar vertebrae (LV) in orchiectomized (ORX) rabbits, a model of male osteoporosis. Adult male rabbits (11 months old) were subjected to sham- (n=20) or ORX-surgery (n=24/group) for 7.5 months before dosing initiated. ORX animals were randomized by LV BMD and dosed with either vehicle (Veh), ODN (1.5 and 6 mg/kg per day, providing approximately one to seven times the clinical exposure respectively), or alendronate (ALN; 300 μg/kg per week, s.c.) for 14 months. Endpoints included in vivo spine DXA, urine, serum collected at baseline and at every 3 months; and ex vivo pQCT and strength testing. Compared to Veh, ODN significantly increased LV BMD (P<0.01) by 9% at 3-months and 19% at 14-months with the 1.5 mg/kg dose, and by 6% at 3-months and 27% at 14-months with the 6mg/kg dose, vs ALN by 9% at 14-months. ODN at both doses and ALN reduced the bone resorption marker helical peptide by 5060% vs Veh. While ALN reduced BSAP, ODN maintained this bone formation marker at comparable levels as in Veh. ODN increased pQCT-based trabecular vBMC by 28 and 38% respectively vs Veh (P<0.001), compared to ALN increased this parameter by 11% (P<0.05). From LV compression testing, significant treatment related increases in multiple strength parameters (peak load, apparent strength, yield load, and yield stress, stiffness) compared to Veh were demonstrated. Peak load was positively correlated with vBMC (R=0.9383, P<0.001). Taken together, this study demonstrated ODN dosed in treatment mode was highly efficacious in restoring lumbar spine bone mass and increasing bone strength of ORX rabbits. Our results support the clinical evaluation of ODN for the treatment of osteoporosis in men.
17 - 20 May 2014
European Calcified Tissue Society